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- Title
Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway.
- Authors
Matushansky, Igor; Hernando, Eva; Socci, Nicholas D.; Mills, Joslyn E.; Matos, Tulio A.; Edgar, Mark A.; Singer, Samuel; Maki, Robert G.; Cordon-Cardo, Carlos
- Abstract
Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. We present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, we show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/beta-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, we illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Our results provide mechanistic insights regarding the cell of origin of MFH, establish what we believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas.
- Subjects
STEM cells; WNT proteins; PROTO-oncogenes; GROWTH factors; L-form bacteria; MESENCHYME; ANIMAL experimentation; CELL differentiation; CELLULAR signal transduction; COMPARATIVE studies; CONNECTIVE tissue cells; CYTOSKELETAL proteins; GLYCOPROTEINS; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; TRANSFERASES; EVALUATION research; GENE expression profiling; CANCER cell culture; CONNECTIVE tissue tumors; NEOPLASTIC cell transformation; PHYSIOLOGY
- Publication
Journal of Clinical Investigation, 2007, Vol 117, Issue 11, p3248
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI31377